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  1. Abstract We present a machine learning framework to automate knowledge discovery through knowledge graph construction, inconsistency resolution, and iterative link prediction. By incorporating knowledge from 10 publicly available sources, we construct an Escherichia coli antibiotic resistance knowledge graph with 651,758 triples from 23 triple types after resolving 236 sets of inconsistencies. Iteratively applying link prediction to this graph and wet-lab validation of the generated hypotheses reveal 15 antibiotic resistant E. coli genes, with 6 of them never associated with antibiotic resistance for any microbe. Iterative link prediction leads to a performance improvement and more findings. The probability of positive findings highly correlates with experimentally validated findings ( R 2  = 0.94). We also identify 5 homologs in Salmonella enterica that are all validated to confer resistance to antibiotics. This work demonstrates how evidence-driven decisions are a step toward automating knowledge discovery with high confidence and accelerated pace, thereby substituting traditional time-consuming and expensive methods.
    Free, publicly-accessible full text available December 1, 2023
  2. The objective of this study is to validate reduced graphene oxide (RGO)-based volatile organic compounds (VOC) sensors, assembled by simple and low-cost manufacturing, for the detection of disease-related VOCs in human breath using machine learning (ML) algorithms. RGO films were functionalized by four different metalloporphryins to assemble cross-sensitive chemiresistive sensors with different sensing properties. This work demonstrated how different ML algorithms affect the discrimination capabilities of RGO–based VOC sensors. In addition, an ML-based disease classifier was derived to discriminate healthy vs. unhealthy individuals based on breath sample data. The results show that our ML models could predict the presence of disease-related VOC compounds of interest with a minimum accuracy and F1-score of 91.7% and 83.3%, respectively, and discriminate chronic kidney disease breath with a high accuracy, 91.7%.
  3. Free, publicly-accessible full text available January 1, 2023
  4. Free, publicly-accessible full text available May 1, 2023
  5. Glutaraldehyde is a widely used biocide on the market for about 50 years. Despite its broad application, several reports on the emergence of bacterial resistance, and occasional outbreaks caused by poorly disinfection, there is a gap of knowledge on the bacterial adaptation, tolerance, and resistance mechanisms to glutaraldehyde. Here, we analyze the effects of the independent selection of mutations in the transcriptional regulator yqhC for biological replicates of Escherichia coli cells subjected to adaptive laboratory evolution (ALE) in the presence of glutaraldehyde. The evolved strains showed improved survival in the biocide (11–26% increase in fitness) as a result of mutations in the activator yqhC , which led to the overexpression of the yqhD aldehyde reductase gene by 8 to over 30-fold (3.1–5.2 log2FC range). The protective effect was exclusive to yqhD as other aldehyde reductase genes of E. coli , such as yahK , ybbO , yghA , and ahr did not offer protection against the biocide. We describe a novel mechanism of tolerance to glutaraldehyde based on the activation of the aldehyde reductase YqhD by YqhC and bring attention to the potential for the selection of such tolerance mechanism outside the laboratory, given the existence of YqhD homologs inmore »various pathogenic and opportunistic bacterial species.« less
  6. Biocide use is essential and ubiquitous, exposing microbes to sub-inhibitory concentrations of antiseptics, disinfectants, and preservatives. This can lead to the emergence of biocide resistance, and more importantly, potential cross-resistance to antibiotics, although the degree, frequency, and mechanisms that give rise to this phenomenon are still unclear. Here, we systematically performed adaptive laboratory evolution of the gut bacteria Escherichia coli in the presence of sub-inhibitory, constant concentrations of ten widespread biocides. Our results show that 17 out of 40 evolved strains (43%) also decreased the susceptibility to medically relevant antibiotics. Through whole-genome sequencing, we identified mutations related to multidrug efflux proteins ( mdfA and acrR ), porins ( envZ and ompR ), and RNA polymerase ( rpoA and rpoBC ), as mechanisms behind the resulting (cross)resistance. We also report an association of several genes ( yeaW , pyrE , yqhC , aes , pgpA , and yeeP - isrC ) and specific mutations that induce cross-resistance, verified through mutation repairs. A greater capacity for biofilm formation with respect to the parent strain was also a common feature in 11 out of 17 (65%) cross-resistant strains. Evolution in the biocides chlorophene, benzalkonium chloride, glutaraldehyde, and chlorhexidine had the most impact inmore »antibiotic susceptibility, while hydrogen peroxide and povidone-iodine the least. No cross-resistance to antibiotics was observed for isopropanol, ethanol, sodium hypochlorite, and peracetic acid. This work reinforces the link between exposure to biocides and the potential for cross-resistance to antibiotics, presents evidence on the underlying mechanisms of action, and provides a prioritized list of biocides that are of greater concern for public safety from the perspective of antibiotic resistance. Significance Statement Bacterial resistance and decreased susceptibility to antimicrobials is of utmost concern. There is evidence that improper biocide (antiseptic and disinfectant) use and discard may select for bacteria cross-resistant to antibiotics. Understanding the cross-resistance emergence and the risks associated with each of those chemicals is relevant for proper applications and recommendations. Our work establishes that not all biocides are equal when it comes to their risk of inducing antibiotic resistance; it provides evidence on the mechanisms of cross-resistance and a risk assessment of the biocides concerning antibiotic resistance under residual sub-inhibitory concentrations.« less
  7. Food ontologies require significant effort to create and maintain as they involve manual and time-consuming tasks, often with limited alignment to the underlying food science knowledge. We propose a semi-supervised framework for the automated ontology population from an existing ontology scaffold by using word embeddings. Having applied this on the domain of food and subsequent evaluation against an expert-curated ontology, FoodOn, we observe that the food word embeddings capture the latent relationships and characteristics of foods. The resulting ontology, which utilizes word embeddings trained from the Wikipedia corpus, has an improvement of 89.7% in precision when compared to the expert-curated ontology FoodOn (0.34 vs. 0.18, respectively, p value = 2.6 × 10 –138 ), and it has a 43.6% shorter path distance (hops) between predicted and actual food instances (2.91 vs. 5.16, respectively, p value = 4.7 × 10 –84 ) when compared to other methods. This work demonstrates how high-dimensional representations of food can be used to populate ontologies and paves the way for learning ontologies that integrate contextual information from a variety of sources and types.
  8. Abstract The network-based proximity between drug targets and disease genes can provide novel insights regarding the repercussions, interplay, and repositioning of drugs in the context of disease. Current understanding and treatment for reversing of the fibrotic process is limited in systemic sclerosis (SSc). We have developed a network-based analysis for drug effects that takes into account the human interactome network, proximity measures between drug targets and disease-associated genes, genome-wide gene expression and disease modules that emerge through pertinent analysis. Currently used and potential drugs showed a wide variation in proximity to SSc-associated genes and distinctive proximity to the SSc-relevant pathways, depending on their class and targets. Tyrosine kinase inhibitors (TyKIs) approach disease gene through multiple pathways, including both inflammatory and fibrosing processes. The SSc disease module includes the emerging molecular targets and is in better accord with the current knowledge of the pathophysiology of the disease. In the disease-module network, the greatest perturbing activity was shown by nintedanib, followed by imatinib, dasatinib, and acetylcysteine. Suppression of the SSc-relevant pathways and alleviation of the skin fibrosis was remarkable in the inflammatory subsets of the SSc patients receiving TyKI therapy. Our results show that network-based drug-disease proximity offers a novel perspective intomore »a drug’s therapeutic effect in the SSc disease module. This could be applied to drug combinations or drug repositioning, and be helpful guiding clinical trial design and subgroup analysis.« less
  9. Interest in animal cell-based meat (ACBM) or laboratory-grown meat has been increasing; however, the economic viability of these potential products has not been thoroughly vetted. Recent studies suggest monoclonal antibody production technology can be adapted for the industrialization of ACBM production. This study provides a scenario-based assessment of the projected cost per kilogram of ACBM produced in the United States based on cellular metabolic requirements and process/chemical engineering conventions. A sensitivity analysis of the model identified the nine most influential cost factors for ACBM production out of 67 initial parameters. The results indicate that technological performance will need to approach technical limits for ACBM to achieve profitably as a commodity. However, the model also suggests that low-volume high-value specialty products could be viable based on current technology.